Our overall hypothesis is that restoration of up-regulated CNS proinflammatory cytokine production back towards homeostasis can provide attenuation of neurodegenerative disease progression. Specific to this proposal, we hypothesize that this common mechanism of pathophysiology progression can be targeted for decreasing neurodegeneration related to acute brain injury, injury related to chronic neurodegenerative disease, and the contribution of prior acute brain injury to increased susceptibility to the second injury. The three paradigms address disease progression in complex disorders, with the two-hit model addressing prior medical history contributions to later stage disease. The proposed research will use bioavailable, novel small molecule compounds developed in the principal investigator's laboratory to modulate the brain proinflammatory cytokine surge that contributes to hippocampal synaptic dysfunction. The in vivo brain injuries include an acute impact injury as a surrogate for traumatic brain injury (TBI), an Alzheimer's disease (AD)-relevant injury using toxic forms of human Abeta, and a two-hit injury model of TBI followed by a later AD-relevant injury. The pathophysiology progression endpoints include proinflammatory cytokine levels, and the neurological outcomes endpoints include changes in synaptic marker proteins and hippocampus-dependent behavior changes. The two-hit injury studies are a way to explore initially the neglected question of how a prior brain injury can be a susceptibility factor for age-onset AD and other neurological disorders, and to directly address the potential for developing new therapies that alter short and long term outcomes of brain injury on later neurological disease susceptibility, onset and progression. The ability of bioavailable small molecules that attenuate the up-regulation of brain proinflammatory cytokine levels and modulate the neurological outcomes of brain injuries will provide an integrative chemical biology demonstration of the causal relationships between this common pathophysiology mechanism and brain dysfunctions. Successful completion of the proposed studies will provide a firm foundation for future clinical investigations that seek to translate a large body of public health data into potential therapeutic intervention paradigms, and provide an immediate stimulus to ongoing clinical development of new classes of potential disease-modifying therapeutics. PUBLIC HEALTH RELEVANCE: Successful completion of the proposed studies will provide a foundation for immediate translation of basic science into potential disease-modifying clinical interventions using new classes of therapeutics.